Building on her postdoctoral training in the molecular genetic abnormalities in colon and pancreatic cancers, this project was developed by Dr. Deborah Dillon with the assistance of her mentor, Dr. Jose Costa, to extend her experience to the characterization of molecular events involved in breast cancer progression. In addition to furthering her technical skills, the work proposed in this grant will broaden her experiences with the addition of pre-clinical and epidemiologic components. Collaborations and interactions with members of basic research and clinical departments, seminars, and laboratory meetings will provide her a network of scientific and intellectual resources upon which to build a foundation for a career as an independent investigator in the fields of molecular pathology, molecular epidemiology and cancer diagnosis. The underlying assumption of the proposed studies is that some of the genetic changes found in advanced tumors are already present in small numbers of cells in the breast epithelium prior to the development of the morphologic changes we currently use to define neoplasia. Using microdissection and other techniques for the demonstration of genetic alterations present in small numbers of cells, she will analyze the diversity and distribution of molecular alterations in p53, p16, K-ras, H-ras, N-ras, Neu, Rb, Cyclin D1 and p27 in non-neoplastic pre-neoplastic and neoplastic human and mouse mammary tissues. She will then analyze these data in the context of fat and calcium intake to test the hypothesis that nutrients differentially promote or protect based on the acquired genotype of the epithelium at risk. The results obtained at the completion of the proposed studies will contribute to a better definition of the relationship between diet and breast tumor genotype. In addition, the proposed studies have the potential to demonstrate and suggest a mechanism for the role of nutrients in the pathogenesis of breast cancer and may point to new avenues of investigation for chemoprevention and other rational treatment strategies.